Disparities in Systemic Classical and Alternative Pathways in Intermediate Age-Related Macular Degeneration Compared to Geographic Atrophy

Abstract

Purpose : Studies have demonstrated a strong association between the complement system and age-related macular degeneration (AMD). The findings have led to several clinical trials targeting local complement dysregulation in AMD. In addition to complement activation in ocular tissues there is activation systemically. This is understudied. The purpose of our study was to examine differences in plasma levels of systemic complement components in a cross-sectional study of patients with intermediate (iAMD), geographic atrophy (GA), and controls using an extensive panel of complement components from the classical (CP), lectin (LP), and alternative pathway (AP) as well as the regulators factor H and I.

Methods : Patients were drawn from an AMD registry. Diagnosis was confirmed with multimodal imaging and classified using the Beckmann and classification of atrophy criteria. Plasma complement factor levels were measured by ELISA and multiplex Luminex immunoassays. Statistical comparisons between groups were performed using linear regression models on rank-transformed values.

Results : We included 365 patients, of which 206 had iAMD, 96 had GA, and 63 had no AMD (controls). Adjusted for age and multiple comparisons, we found significant dysregulation of many complement components across cases and controls (Table 1). Regarding the AP, median level of Factor B was lower in GA compared to controls and iAMD indicating higher consumption. The C3a/C3 ratio was lower in GA. In terms of the CP, levels of C4 and C2 were higher in GA compared to controls and iAMD. Notably, (Fig 1), we found a stepwise decline in the levels of the major regulators, Factor I and Factor H when comparing each group.

Conclusions : We found substantial changes in levels of systemic complement components when comparing controls and patients with iAMD and GA. Our study demonstrates lower CP consumption associated with GA and supports previous data suggesting higher AP activation is associated with worse AMD. Despite the higher AP consumption, overall complement activity, represented by C3a/C3, remains lower in GA. Our study suggests that there might be a crucial role for the CP in the pathogenesis of AMD and might explain why the response to anti-complement therapy differs among patients with GA.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

 

Complement levels across groups

 

Boxplot demonstrating systemic levels of Factor I and Factor H across groups